6H-oxazolo[4,5-e]indole derivatives as nicotinic acetylcholine receptor ligands and/or serotonergic ligands

ABSTRACT

Compounds of the formula I in which R 1 , R 2 , R 3  and R 4  are as defined in claim  1,  are ligands of the nicotinic acetylcholine receptor and/or serotonergic ligands and are suitable for the prophylaxis or treatment of psychoses, schizophrenia, depression, anxiety states, dementia, in particular Alzheimer&#39;s disease and Lewy bodies dementia, neurodegenerative disorders, Parkinson&#39;s disease, amyotrophic lateral sclerosis, Huntington&#39;s disease, Tourette&#39;s syndrome, learning and memory restrictions, bulimia anorexia nervosa or other eating disorders, compulsvie behaviour, premenstrual syndrome, age-induced memory impairment, amelioration of withdrawal symptoms in nicotine dependence, strokes or brain damage by toxic compounds, and for the treatment of disorders which are characterised by an excess of circulating serotonin or by serotonergic hyperactivity.

The invention relates to 6H-oxazolo[4,5-e]indole derivatives of theformula I

in which

-   -   R¹ is H or Het¹,    -   R² is H, A, cycloalkyl, —(CH₂)_(p)—N(R⁵)₂, —(CH₂)_(p)—OR⁵,        —(CH₂)_(n)—Ar or —(CH₂)_(n)-Het,    -   R³ is H, Hal, OH, OA or O—(CH₂)_(n)—Ar,    -   R⁴ is H, A or —(CH₂)_(n)—Ar,    -   R⁵ is H or A,    -   A is a linear or branched alkyl group having from 1 to 10 carbon        atoms,    -   Ar is phenyl, naphthyl or biphenyl, each of which is        unsubstituted or monosubstituted or polysubstituted by Hal, A,        OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COR⁵, NR⁵CON(R⁵)₂,        NR⁵SO₂A, COR⁵, SO₂NR⁵ or S(O)_(m)A,    -   cycloalkyl is cycloalkyl having from 3 to 10 carbon atoms,    -   Hal is F, Cl, Br or I,    -   Het is a saturated, unsaturated or aromatic monocyclic or        bicyclic heterocyclic radical having from 5 to 10 ring members,        which may contain from 1 to 4 N and/or from 1 to 4 S and/or from        1 to 4 O atoms, and in which the heterocyclic radical may be        monosubstituted, disubstituted or trisubstituted by Hal, A,        —[C(R⁵)₂]_(o)—Ar, —[C(R⁵)₂]_(o)-cycloalkyl, OR⁵, N(R⁵)₂, NO₂,        CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵CON(R⁵)₂, NR⁵SO₂A, COR⁵, SO₂NR⁵        or S(O)_(m)A and/or carbonyl oxygen,    -   Het¹ is a saturated, unsaturated or aromatic monocyclic,        bicyclic or tricyclic heterocyclic radical having from 5 to 10        ring members which contains at least 1 N atom and in which the        heterocyclic radical may be monosubstituted, disubstituted or        trisubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN and/or carbonyl        oxygen,    -   n is 0, 1, 2, 3, 4, 5, 6, 7 or 8,    -   m is 1 or 2,    -   o is 0, 1, 2, 3 or 4,    -   p is 1, 2, 3, 4, 5, 6, 7 or 8,    -   and their physiologically acceptable salts and solvates.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been found that the compounds of the formula I and theirphysiologically acceptable salts and solvates are well tolerated andhave valuable pharmacological properties since they act on the centralnervous system. The compounds are nicotinic acetylcholine receptorligands and/or serotonergic ligands.

Of the well-characterised class of acetylcholine receptors, some membershave been implicated in certain disorders of the central nervous system.Known active ingredients which are able to interact with theacetylcholine receptor class are, for example, pilocarpine, nicotine,lobeline and epibatidine.

These nicotinic acetylcholine receptors can be divided into two mainclasses, depending on the sites at which they occur.

The first class comprises the neuromuscular receptors. These aresubdivided into (α₁α₁βεδ) and (α₁α₁βγδ) receptors. The second classcomprises the neuronal nicotinic acetylcholine receptors, which arefound in the ganglia. In these, a distinction is made between the(β₂-β₅)receptors and the (α₂-α₉) receptors, in this respect see also“Basic Neurochemistry”, Ed. Siegel et al., Raven Press, New York, 1993.

The substances of the formula I are capable of interacting with each ofthese receptors. The substances of the formula I interact particularlywell with the nicotinic α₇ receptor.

In-vitro evidence of the interaction with the nicotinic α₇ receptor canbe obtained, for example, analogously to J. M. Ward et al., FEB 1990,270, 45-48 or D. R. E. Macallan, FEB 1998, 226, 357-363.

Further in-vitro tests for nicotinic receptors are described in F. E.D'Amour et al., Manual for Laboratory Work in Mammalian Physiology, 3rdEd., The University of Chicago Press (1965), W. Sihver et al.,Neuroscience 1998, 85, 1121-1133 or B. Latli et al., J. Med. Chem. 1999,42, 2227-2234.

Serotonergic ligands are ligands of the 5-HT₃ receptor and/or of the5-HT₆ receptor.

5-HT₆ receptors form a sub-family of 5-HT receptors. Theneurotransmitter 5-hydroxytryptamine (5-HT), also known as serotonin, isan important regulatory neurotransmitter in the brain whose actions aresupported by a family of receptors, which, as far as we know today,contain 13 G-protein-coupled receptors and an ion channel.

The greatest density of serotonin 5-HT₆ receptors in the brain is foundin the tuberculum olfactorium, in the nucleus accumbens, in thestriatum, in the gyrus dentatus and in the CA1-3 regions of thehippocampus. These regions are involved to a particularly great extentin psychiatric disorders, such as, for example, schizophrenia ordepression. In addition, it is known from animal experiments thatadministration of 5-HT₆ antisense oligo-nucleotides causes a behavioursyndrome which corresponds to that of dopamine agonists. Furthermore,hyperactivity of the dopaminergic neurotransmitter system ispathophysiologically safeguarded in schizophrenia (dopamine hypothesisof schizophrenia). However, dysfunctions of the dopamine system havealso been found in various clinical forms of depression. In addition, alarge number of the established and also more recent therapeutic agentsemployed for the treatment of these psychiatric disorders in clinicalpractice bind to the 5-HT₆ receptor. Particular mention may be made hereof atypical neuroleptics (for example clozapine) and the tricyclicantidepressants (for example amitriptyline).

In addition, it has been found in studies involving animal experimentsthat 5-HT₆ receptors in the brain control cholinergic neurotransmission.Cholinergics are employed in illnesses with memory disorders, such as,for example, Alzheimer's disease.

The efficacy of the compounds of the formula I as inhibitors of the5-HT₃ receptor can be determined by the method of Richardson et al.,Nature 1985, 316, 126 or by the method of Watling et al., European J.Pharmacol. 1988, 149, 397. Here, the compounds antagonise the action ofserotonin at 5-HT₃ receptors, such as, for example, theserotonin-induced Bezold-Jarisch reflex (method, see J. Pharm.Pharmacol., 1980, 40, 301-302 and Nature 316, 126-131). In addition,these compounds displace the substance ³H-GR65630, which is known as aselective 5-HT₃ ligand, from the homogenised tissue from the endorhinalcortex of rats (see Europ. J. Pharmacol., 1989, 159, 157-164).

Illnesses which can be treated with the substances of the formula I thusinclude psychoses, schizophrenia, depression, anxiety states, dementia,in particular Alzheimer's disease and Lewy bodies dementia,neurodegenerative disorders, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's disease, Tourette's syndrome, learning andmemory restrictions, bulimia, anorexia nervosa or other eatingdisorders, compulsive behaviour, premenstrual syndrome, age-inducedmemory impairment, and amelioration of withdrawal symptoms in nicotinedependence. Owing to their neuroprotective action, compounds of theformula I are used in strokes and brain damage by toxic compounds. Thecompounds of the formula I and their physiologically acceptable saltsare therefore suitable as therapeutic active ingredients for disordersof the central nervous system.

The compounds are suitable for the treatment of disorders which arecharacterised by an excess of circulating serotonin or by serotonergichyperactivity. These include, in particular, psychoses, nausea andvomiting (occurring, for example, during chemotherapeutic orradiotherapeutic treatment of cancer diseases), irritable bowelsyndrome, dementia or other cognitive disorders, migraine and addictionillnesses.

Compounds of the formula I and their salts and solvates are alsosuitable as intermediates for the preparation of other medicament activeingredients.

The invention relates to the compounds of the formula I and to theirphysiologically acceptable acid-addition salts. The invention alsorelates to the solvates, for example hydrates or alcoholates, of thesecompounds.

The term “solvates of the compounds of the formula I” is taken to meanadducts of inert solvent molecules onto the compounds of the formula Iwhich form owing to their mutual attractive force. Solvates are, forexample, monohydrates or dihydrates or addition compounds with alcohols,such as, for example, with methanol or ethanol.

Should radicals which have an asymmetrical carbon atom which can havedifferent configurations be introduced via the radicals R¹ to R⁴, forexample 1-azabicyclo[2.2.2]oct-3-yl for R¹, the compounds of the formulaI may exist in various optically active forms or alternatively asracemates or racemate mixtures.

The invention relates to the compounds of the formula I and their saltsand solvates according to Claim 1 and to a process for the preparationof compounds of the formula I and their salts and solvates,characterised in that

-   -   a compound of the formula II    -   in which R¹, R³ and R⁴are as defined in Claim 1,    -   is reacted with a compound of the formula III        H₂N—CH₂—R²   III,    -   in which    -   R² is as defined in Claim 1,    -   in the presence of an oxidant, and    -   if desired, the radical R¹═H is converted into another radical        R¹ as defined in Claim 1,    -   and/or    -   a base of the formula I obtained is converted into one of its        salts by treatment with an acid.

The invention also relates to the compounds of the formula I accordingto Claim 1 and their physiologically acceptable salts and solvates asmedicament active ingredients.

The invention likewise relates to the compounds of the formula Iaccording to Claim 1 and their physiologically acceptable salts orsolvates as ligands of the nicotinic acetylcholine receptor.

The invention likewise relates to the compounds of the formula Iaccording to Claim 1 and their physiologically acceptable salts orsolvates as serotonergic ligands.

For all radicals which may occur more than once, such as, for example, Aor Hal, their meanings are independent of one another.

A is linear or branched alkyl having from 1 to 10 carbon atoms andpreferably has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Alkylhaving from 1 to 10 carbon atoms is preferably methyl, furthermoreethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl,furthermore also n-pentyl, 1-, 2- or 3-methylbutyl, n-hexyl, 1-, 2-, 3-or 4-methylpentyl, n-heptyl, 1-, 2-, 3- or 4-ethylpentyl, n-octyl,n-nonyl or n-decyl.

Alkyl is particularly preferably methyl, isopropyl, n-propyl or1-ethylpentyl.

Ar is phenyl, naphthyl or biphenyl, each of which is unsubstituted ormonosubstituted or polysubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN,COOR⁵, CON(R⁵)₂, NR⁵COR⁵, NR⁵CON(R⁵)₂, NR⁵SO₂A, COR⁵, SO₂NR⁵, SO₂NR⁵ orS(O)_(m)A, where A has one of the meanings indicated above, and R⁵ and mhave one of the meanings indicated below.

Ar is preferably unsubstituted or substituted phenyl, naphthyl orbiphenyl, specifically preferably phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butyl-phenyl, o-, m- or p-trifluoromethylphenyl, o-, m-or p-aminophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl,o-, m- or p-(trifluoromethoxy)phenyl, o-, m- or p-cyanophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-,m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(difluoromethoxy)phenyl, o-, m- or p-(fluoromethoxy)phenyl,furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-,2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-,2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-,2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-,2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-,2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-,3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,2,4,6-tri-tert-butyl-phenyl, furthermore preferably2-nitro-4-(trifluoromethyl)phenyl, 3,5-di(trifluoromethyl)phenyl,2,5-dimethylphenyl, 2-hydroxy-3,5-dichlorophenyl, 2-fluoro-5- or4-fluoro-3-(trifluoromethyl)phenyl, 4-chloro-2- or4-chloro-3-(trifluoromethyl)-, 2-chloro-4- or2-chloro-5-(trifluoromethyl)phenyl, 4-bromo-2- or4-bromo-3-(trifluoromethyl)phenyl, p-iodophenyl,2-nitro-4-methoxyphenyl, 2,5-dimethoxy-4-nitrophenyl,2-methyl-5-nitrophenyl, 2,4-dimethyl-3-nitrophenyl,4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethylphenyl,2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl,2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl or2,4,6-triisopropylphenyl.

Ar is particularly preferably, i.e. —(CH₂)_(n)—Ar where n=0, phenyl oro-methoxyphenyl.

—(CH₂)_(n)—Ar is arylalkyl if Ar has one of the meanings indicated aboveand n is 1, 2, 3, 4, 5, 6, 7 or 8. —(CH₂)_(n)—Ar where n≠0 is preferablybenzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl,phenylhexyl, phenylheptyl, naphthylmethyl, naphthylethyl, naphthylpropylor naphthylbutyl. —(CH₂)_(n)—Ar is particularly preferably benzyl orphenylethyl.

Cycloalkyl having from 3 to 10 carbon atoms is preferably cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or2,6,6-trimethyl-bicyclo[3.1.1]heptyl.

Cycloalkyl is likewise a monocyclic or bicyclic terpene, preferablyp-menthane, menthol, pinane, bornane or camphor, including all knownstereoisomeric forms, or adamantyl. For camphor, this is eitherL-camphor or D-camphor.

Cycloalkyl is particularly preferably2,6,6-trimethylbicyclo[3.1.1]heptyl.

Hal is fluorine, chlorine, bromine or iodine, particularly preferablyfluorine, chlorine or bromine.

Het is a saturated, unsaturated or aromatic monocyclic or bicyclicheterocyclic radical having from 5 to 10 ring members, which may containfrom 1 to 4 N and/or from 1 to 4 S and/or from 1 to 4 O atoms and inwhich the heterocyclic radical may be monosubstituted, disubstituted ortrisubstituted by Hal, A, —[C(R⁵)₂]_(o)—Ar, —[C(R⁵)₂]_(o)-cycloalkyl,OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵CON(R⁵)₂, NR⁵SO₂A,COR⁵, SO₂NR⁵ or S(O)_(m)A and/or carbonyl oxygen, where A, Hal, Ar andcycloalkyl have one of the meanings indicated above, and R⁵, o and m areas defined below.

Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,1,2,4-triazol-1-, 4- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or-5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-,5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl,pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-1H-indolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl,benzo-1,3-dioxol-5-yl, -6-yl, -7-yl or -4-yl, 2-, 4-, 5-, 6- or7-benzothiazolyl, 4- or 5-benzothiadiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 1-, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-,7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-,6-, 7- or 8-quinazolinyl. The heterocyclic radicals may also bepartially or fully hydrogenated. Het may thus also be 2,3-dihydro-2-,-3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl,tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or-3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or -4-imidazolyl,2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6- or -7-1H-indolyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl,1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or 4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-2-, -3-,-4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5-, -6-, -7- or -8-isoquinolinyl.

Het is particularly preferably 2- or 3-thienyl, imidazol-1-yl,pyridin-3-yl, benzothien-3-yl, 6-methoxy-1H-indol-3-yl,benzo-1,3-dioxol-5-yl, tetrahydrofuran-2-yl, morpholin-4-yl,4-methylpiperazin-1-yl or 2-oxopyrrolidin-1-yl.

—(CH₂)_(n)-Het is particularly preferably pyridin-3-yl, thien-2-yl,benzo-1,3-dioxol-5-yl, tetrahydrofuran-2-yl, benzothien-3-yl,thien-3-ylmethyl, 6-methoxy-1H-indol-3-ylmethyl, morpholin-4-ylethyl,2-oxopyrrolidin-1-ylethyl, (4-methyl)piperidin-1-ylethyl orimidazol-1-ylethyl.

Het¹ is a saturated, unsaturated or aromatic monocyclic, bicyclic ortricyclic heterocyclic radical having from 5 to 10 ring members whichcontains at least 1 N atom and in which the heterocyclic radical may bemonosubstituted, disubstituted or trisubstituted by Hal, A, OR⁵, N(R⁵)₂,NO₂, CN and/or carbonyl oxygen, where A is as defined above, and R⁵ isas defined below.

Het¹ is preferably substituted or unsubstituted 1-, 2- or 3-pyrrolyl,1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl,2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 3- or 4-pyridazinyl,pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-1H-indolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 1-, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or8-isoquinolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 1-, 4-, 5-, 6-, 7-or 8-phthalazinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 4-, 5-, 6-,7- or 8-quinazolinyl. The heterocyclic radicals may also be partially orfully hydrogenated. Het¹ may thus also be 2,3-dihydro-1-, -2-, -3-, -4-or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6- or -7-1H-indolyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or-4-pyrazolyl, 1,5-dihydroimidazol-4-on-2- or -5-yl, 1,4-dihydro-1-, -2-,-3- or 4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, tetrahydro-2-, -3- or-4-pyranyl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4-or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl or1-azabicyclo[2.2.2]oct-3-yl. A synonym for 1-azabicyclo[2.2.2]oct-3-ylis quinuclidin-3-yl.

The said heterocyclic rings may also be monosubstituted or disubstitutedby ═O or NHR⁵.

Het¹ is particularly preferably 1-azabicyclo[2.2.2]oct-3-yl,piperidin-3-yl, piperidin-4-yl or 1-methylpiperidin-4-yl.

R¹ is hydrogen or Het¹, where Het¹ is as defined above.

R¹ is preferably hydrogen, 1-azabicyclo[2.2.2]oct-3-yl, piperidin-3-yl,piperidin-4-yl or 1-methylpiperidin-4-yl.

R² is H, A, cycloalkyl, —(CH₂)_(p)—N(R⁵)₂, —(CH₂)_(p)—OR⁵, —(CH₂)_(n)—Aror —(CH₂)_(n)-Het, where R⁵ is as defined below, and n may be 0, 1, 2,3, 4, 5, 6, 7 or 8 and p is 1, 2, 3, 4, 5, 6, 7 or 8. A, cycloalkyl, Arand Het have the preferred and particularly preferred meanings indicatedabove.

n is preferably 0, 1 or 2.

p is preferably 1 or 2.

R² is preferably hydrogen, A, cycloalkyl, phenyl, o-methoxyphenyl,pyridin-3-yl, thien-2-yl, benzo-1,3-dioxol-5-yl, tetrahydrofuran-2-yl,benzothien-3-yl, methoxymethyl, thien-3-ylmethyl,6-methoxy-1H-indol-3-ylmethyl, 2-dimethylaminoethyl,morpholin-4-ylethyl, 2-oxopyrrolidin-1-ylethyl,(4-methyl)piperidin-1-ylethyl or imidazol-1-ylethyl.

R³ is H, Hal, OH, OA or O—(CH₂)_(n)—Ar, where Hal, A, Ar and n are asdefined above.

R³ is preferably hydrogen.

R⁴ is H, A or O—(CH₂)_(n)—Ar, where A, Ar and n are as defined above.

R⁴ is preferably hydrogen.

R⁵ is H or A, where A is as defined above.

—(CH₂)_(p)—OR⁵ is particularly preferably methoxymethyl.

—(CH₂)_(p)—N(R⁵)₂ is particularly preferably 2-dimethylaminoethyl.

m is 1 or 2, where m is preferably 2.

o is 0, 1, 2, 3 or 4. o is preferably 0 or 1.

The invention accordingly relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ij, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   -   in Ia R⁴ is hydrogen;    -   in Ib R³ is hydrogen;    -   in Ic R³ is hydrogen and        -   R⁴ is hydrogen;    -   in Id R¹ is hydrogen;    -   in Ie R¹ is Het¹;    -   in If R¹ is hydrogen, 1-azabicyclo[2.2.2]oct-3-yl,        piperidin-3-yl, piperidin-4-yl or 1-methylpiperidin-4-yl;    -   in Ig R¹ is hydrogen,        -   R² is hydrogen, —(CH₂)_(n)-Het or —(CH₂)_(p)—N(R⁵)₂,        -   R³ is hydrogen,        -   R⁴ is hydrogen and        -   R⁵ is A;    -   in Ih R¹ is 1-azabicyclo[2.2.2]oct-3-yl,        -   R² is hydrogen, A, cycloalkyl, —(CH₂)_(n)—Ar,            —(CH₂)_(p)—OR⁵, —(CH₂)_(n)-Het or —(CH₂)_(p)—N(R⁵)₂,        -   R³ is hydrogen,        -   R⁴ is hydrogen and        -   R⁵ is A;    -   in Ii R¹ is piperidin-4-yl or 1-methylpiperidin-4-yl,        -   R² is hydrogen, A, —(CH₂)_(n)—Ar, —(CH₂)_(n)-Het or            —(CH₂)_(p)—N(R⁵)₂,        -   R³ is hydrogen,        -   R⁴ is hydrogen and        -   R⁵ is A;    -   in Ij R² is hydrogen, A, cycloalkyl, phenyl, o-methoxyphenyl,        pyridin-3-yl, thien-2-yl, benzo-1,3-dioxol-5-yl,        tetrahydrofuran-2-yl, benzothien-3-yl, methoxymethyl,        thien-3-ylmethyl, 6-methoxy-1H-indol-3-ylmethyl,        2-dimethylaminoethyl, morpholin-4-yl-ethyl,        2-oxopyrrolidin-1-ylethyl, (4-methyl)piperidin-1-ylethyl or        imidazol-1-ylethyl.

The invention relates, in particular, to the compounds according toClaim 6 and their salts and solvates.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der Organischen Chemie [Methods of OrganicChemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, JohnWiley & Sons, Inc., New York), to be precise under reaction conditionsas are known and suitable for the said reactions. Use can also be madehere of variants which are known per se, but are not mentioned here ingreater detail.

The starting materials for the claimed process can also be formed insitu by not isolating them from the reaction mixture, but insteadimmediately converting them further into the compounds of the formula I.On the other hand, it is possible to carry out the reaction in steps.

The compounds of the formula I can preferably be obtained by reactingcompounds of the formula II, in which R¹, R³ and R⁴ are as defined inClaim 1, with compounds of the formula III, in which R² is as defined inClaim 1.

Compounds of the formula II and their preparation are disclosed in EP450 345 (EP 450 345 B1: column 3, line 8, to column 4, line 38). EP 450345 is hereby incorporated by way of reference.

The amines of the formula III are generally known or are commerciallyavailable; the compounds of the formula III which are not known caneasily be prepared analogously to the known compounds.

The reaction of compounds of the formula II with amines of the formulaIII is carried out in the presence of an oxidant.

Suitable oxidants are manganese oxide (MnO₂), hydrogen peroxide (H₂O₂),ozone (O₃), potassium permanganate, chromium oxide, sodium chromate orpotassium chromate.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, suchas ethylene glycol monomethyl or monoethyl ether, ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, N-methylpyrrolidone (NMP), dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Depending on the conditions used, the reaction temperature is betweenabout −10° and 150°, normally between 0 and 130°, preferably between 0°and 50°, particularly preferably room temperature.

Depending on the conditions used, the reaction time is between a fewminutes and several days.

A base of the formula I obtained can be converted into the associatedacid-addition salt using an acid. Suitable acids for this reaction arethose which give physiologically acceptable salts. Thus, it is possibleto use inorganic acids, for example sulfuric acid, hydrohalic acids,such as hydrochloric acid or hydrobromic acid, phosphoric acids, such asorthophosphoric acid, nitric acid, sulfamic acid, furthermore organicacids, specifically aliphatic, alicyclic, araliphatic, aromatic orheterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuricacids, such as formic acid, acetic acid, propionic acid, pivalic acid,diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid,salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid,ascorbic acid, nicotinic acid, isonicotinic acid, methane- orethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and-disulfonic acids and laurylsulfuric acid.

The free bases of the formula I can, if desired, be liberated from theirsalts by treatment with strong bases, such as sodium hydroxide,potassium hydroxide, sodium carbonate or potassium carbonate, so long asno further acidic groups are present in the molecule.

The invention furthermore relates to the medicament active ingredientsaccording to the invention as nicotinic acetylcholine receptor ligandsand/or serotonergic ligands for the prophylaxis or treatment ofschizophrenia, depression, anxiety states, dementia, Alzheimer'sdisease, Lewy bodies dementia, neurodegenerative disorders, Parkinson'sdisease, Huntington's disease, Tourette's syndrome, learning and memoryrestrictions, age-induced memory impairment, amelioration of withdrawalsymptoms in nicotine dependence, strokes or brain damage by toxiccompounds.

The invention furthermore relates to pharmaceutical preparationscomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts or solvates. The compounds of theformula I here can be converted into a suitable dosage form togetherwith at least one solid, liquid and/or semi-liquid excipient or adjuvantand if desired in combination with one or more further activeingredients.

These preparations can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and which do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, suchas lactose or starch, magnesium stearate, talc and Vaseline. Suitablefor oral administration are, in particular, tablets, pills, coatedtablets, capsules, powders, granules, syrups, juices or drops, suitablefor rectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders. The novel compounds mayalso be lyophilised and the resultant lyophilisates used, for example,for the preparation of injection preparations. The preparationsindicated may be sterilised and/or comprise adjuvants, such aslubricants, preservatives, stabilisers and/or wetting agents,emulsifiers, salts for modifying the osmotic pressure, buffersubstances, colorants, flavours and/or a plurality of further activeingredients, for example one or more vitamins.

The substances according to the invention are generally administeredanalogously to known, commercially available preparations (for exampleTae-rin), preferably in doses of between about 5 mg and 100 mg, inparticular between 10 and 40 mg per dosage unit. The daily dose ispreferably between about 0.5 and 1 mg/kg of body weight.

The specific dose for each individual patient depends on a very widevariety of factors, for example on the efficacy of the specific compoundemployed, on the age, body weight, general state of health, sex, on thediet, on the time and method of administration, on the excretion rate,medicament combination and severity of the particular disorder to whichthe therapy applies.

Oral administration is preferred.

The above-mentioned compounds of the formula I are used for thepreparation of medicaments, in particular medicaments which are employedfor the treatment of disorders based on dysfunction of nicotinicacetylcholine receptors.

The invention likewise relates to the use of compounds of the formula Iaccording to Claim 1 and/or their physiologically acceptable salts orsolvates for the preparation of a medicament, in particular for thepreparation of a medicament for the treatment of disorders in which thebinding to nicotinic acetylcholine receptors results in an improvementin the clinical picture.

The invention furthermore relates to the use of compounds of the formulaI according to Claim 1 and/or of their physiologically acceptable saltsand solvates for the preparation of a medicament for the prophylaxis ortreatment of psychoses, schizophrenia, depression, anxiety states,dementia, in particular Alzheimer's disease and Lewy bodies dementia,neurodegenerative disorders, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's disease, Tourette's syndrome, learning andmemory restrictions, bulimia, anorexia nervosa or other eatingdisorders, compulsive behaviour, premenstrual syndrome, age-inducedmemory impairment, amelioration of withdrawal symptoms in nicotinedependence, strokes or brain damage by toxic compounds.

The invention furthermore relates to the use of compounds of the formulaI according to Claim 1 and/or of their physiologically acceptable saltsand solvates for the preparation of a medicament for the treatment ofdisorders that are characterised by an excess of circulating serotoninor by serotonergic hyperactivity, in particular of nausea or vomiting.

Even without further details, it is assumed that a person skilled in theart will be able to use the above description in the broadest scope. Thepreferred embodiments should therefore merely be regarded as descriptivedisclosure which is absolutely not limiting in any way.

Above and below, all temperatures are given in ° C. In the followingexamples, “conventional work-up” means that, if necessary, the solventis removed, water is added if necessary, the pH is, if necessary,adjusted to between 2 and 10, depending on the constitution of the endproduct, the mixture is extracted with ethyl acetate or dichloromethane,the phases are separated, the organic phase is dried over sodiumsulfate, filtered and evaporated, and the product is purified bychromatography on silica gel and/or by crystallisation. The purifiedcompounds are, if desired, freeze-dried.

Mass spectrometry (MS): ESI (electrospray ionisation) (M+H)⁺

EXAMPLE 1

0.5 mmol of methylamine and 4.13 mmol of MnO₂ are added to a solution of0.4 mmol of 5-hydroxy-1H-indole in 3 ml of DMF, and the mixture isstirred at room temperature for 18 hours. The suspension is filteredthrough Celite and subjected to conventional work-up, giving6H-oxazolo-[4,5-e]indole; ESI 159.

Reaction of the free base with 1 N HCl solution in methanol gives6H-oxazolo[4,5-e]indole hydrochloride.

EXAMPLE 2

Analogously to Example 1, reaction of 5-hydroxy-1H-indole with

-   -   N¹,N¹-dimethylpropane-1,3-diamine gives        dimethyl[2-(6H-oxazolo[4,5-e]indol-2-yl)ethyl]amine; ESI 230;        salt precipitation with 1N HCl solution gives        dimethyl[2-(6H-oxazolo[4,5-e]indol-2-yl)ethyl]amine        hydrochloride,    -   3-imidazol-1-ylpropylamine gives        2-(2-imidazol-1-ylethyl)-6H-oxazolo[4,5-e]indole; ESI 253; salt        precipitation with 1N HCl solution gives        2-(2-imidazol-1-ylethyl)-6H-oxazolo[4,5-e]indole hydrochloride,    -   3-(4-methylpiperazin-1-yl)propylamine gives        2-[2-(4-methylpiperazin-1-yl)ethyl]-6H-oxazolo[4,5-e]indole; ESI        285; salt precipitation with 1N HCl solution gives        2-[2-(4-methylpiperazin-1-yl)ethyl]-6H-oxazolo[4,5-e]indole        hydrochloride,    -   3-morpholin-4-ylpropylamine gives        2-(2-morpholin-4-ylethyl)-6H-oxazolo[4,5-e]indole; ESI 272; salt        precipitation with 1N HCl solution gives        2-(2-morpholin-4-ylethyl)-6H-oxazolo[4,5-e]indole hydrochloride,    -   1-(3-aminopropyl)pyrrolidin-2-one        1-[2-(6H-oxazolo[4,5-e]indol-2-yl)ethyl]pyrrolidin-2-one; ESI        270; salt precipitation with 1N HCl solution gives        1-[2-(6H-oxazolo[4,5-e]indol-2-yl)ethyl]pyrrolidin-2-one        hydrochloride,    -   C-pyridin-3-ylmethylamine gives        2-pyridin-3-yl-6H-oxazolo[4,5-e]indole; ESI 236; salt        precipitation with 1N HCl solution gives        2-pyridin-3-yl-6H-oxazolo[4,5-e]indole hydrochloride;    -   2-(6-methoxy-1H-indol-3-yl)ethylamine gives        2-(6-methoxy-1H-indol-3-ylmethyl)-6H-oxazolo[4,5-e]indole; ESI        318; salt precipitation with 1N HCl solution gives        2-(6-methoxy-1H-indol-3-ylmethyl)-6H-oxazolo[4,5-e]indole        hydrochloride.

EXAMPLE 3

Analogously to Example 1, reaction of3-(5-hydroxy-1H-indol-3-yl)-1-aza-bicyclo[2.2.2]octane with

-   -   butylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-propyl-6H-oxazolo[4,5-e]indole;        ESI 310; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-propyl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   benzylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-phenyl-6H-oxazolo[4,5-e]indole;        ESI 344; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-phenyl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   3-morpholin-4-ylpropylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-morpholin-4-ylethyl)-6H-oxazolo[4,5-e]-indole;        ESI 381; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-morpholin-4-ylethyl)-6H-oxazolo[4,5-e]-indole        hydrochloride;    -   C-benzo[b]thiophen-3-ylmethylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzo[b]thiophen-3-yl-6H-oxazolo[4,5-e]-indole;        ESI 401; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzo[b]thiophen-3-yl-6H-oxazolo[4,5-e]-indole        hydrochloride;    -   2-(6-methoxy-1H-indole-3-yl)ethylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl-2-(5-methoxy-1H-indol-3-ylmethyl)-6H-oxazolo[4,5-e]indole;        ESI 428; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl-2-(5-methoxy-1H-indol-3-ylmethyl)-6H-oxazolo[4,5-e]indole        hydrochloride;    -   C-(tetrahydrofuran-3-yl)methylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(tetrahydrofuran-2-yl)-6H-oxazolo[4,5-e]-indole;        ESI 338; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(tetrahydrofuran-2-yl)-6H-oxazolo[4,5-e]-indole        hydrochloride;    -   3-(4-methylpiperazin-1-yl)propylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-[2-(4-methylpiperazin-1-yl)ethyl]-6H-oxazolo[4,5-e]indole;        ESI 395; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-[2-(4-methylpiperazin-1-yl)ethyl]-6H-oxazolo[4,5-e]indole        hydrochloride;    -   3-imidazol-1-ylpropylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-2-imidazol-1-ylethyl)-6H-oxazolo[4,5-e]-indole;        ESI 362; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-imidazol-1-ylethyl)-6H-oxazolo[4,5-e]-indole        hydrochloride;    -   2-ethylhexylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-ethylpentyl)-6H-oxazolo[4,5-e]indole;        ESI 367; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-ethylpentyl)-6H-oxazolo[4,5-e]indole        hydrochloride;    -   2-methoxybenzylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-methoxyphenyl)-6H-oxazolo[4,5-e]-indole;        ESI 374; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-methoxyphenyl)-6H-oxazolo[4,5-e]-indole        hydrochloride;    -   2-methoxyethylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxymethyl-6H-oxazolo[4,5-e]indole;        ESI 312; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxymethyl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   ethylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-6H-oxazolo[4,5-e]indole;        ESI 282; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   Isobutylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-isopropyl-6H-oxazolo[4,5-e]indole;        ESI 310; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-isopropyl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   C-benzo-1,3-dioxol-5-ylmethylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzo-1,3-dioxol-5-yl-6H-oxazolo[4,5-e]-indole;        ESI 388; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzo-1,3-dioxol-5-yl-6H-oxazolo[4,5-e]-indole        hydrochloride;    -   1-(3-aminopropyl)pyrrolidin-2-one gives        1-{2-[8-(1-azabicyclo[2.2.2]oct-3-yl)-6H-oxazolo[4,5-e]indol-2-yl]ethyl}-pyrrolidin-2-one;        ESI 379; salt precipitation with 1N HCl solution gives        1-{2-[8-(1-azabicyclo[2.2.2]oct-3-yl)-6H-oxazolo[4,5-e]indol-2-yl]ethyl}-pyrrolidin-2-one        hydrochloride;    -   C-(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)methylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)-6H-oxazolo[4,5-e]indole;        ESI 405; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)-6H-oxazolo[4,5-e]indole        hydrochloride;    -   methylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-6H-oxazolo[4,5-e]indole; ESI        268; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-6H-oxazolo[4,5-e]indole        hydrochloride;    -   2-thiophen-2-ylethylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-thiophen-2-ylmethyl-6H-oxazolo[4,5-e]-indole;        ESI 364; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-thiophen-2-ylmethyl-6H-oxazolo[4,5-e]-indole        hydrochloride;    -   C-pyridin-3-ylmethylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-pyridin-3-yl-6H-oxazolo[4,5-e]indole;        ESI 345; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-pyridin-3-yl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   N¹,N¹-dimethylpropane-1,3-diamine gives        {2-[8-(1-azabicyclo[2.2.2]oct-3-yl)-6H-oxazolo[4,5-e]indol-2-yl]ethyl}-dimethylamine;        ESI 339; salt precipitation with 1N HCl solution gives        {2-[8-(1-azabicyclo[2.2.2]oct-3-yl)-6H-oxazolo[4,5-e]indol-2-yl]ethyl)-dimethylamine        hydrochloride;    -   2-(6-methoxy-1H-indol-3-yl)ethylamine gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(6-methoxy-1H-indol-3-ylmethyl)-6H-oxazolo[4,5-e]indole;        ESI 428; salt precipitation with 1N HCl solution gives        8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(6-methoxy-1H-indol-3-ylmethyl)-6H-oxazolo[4,5-e]indole        hydrochloride.

EXAMPLE 4

Analogously to Example 1, reaction of3-(1-methylpiperidin-4-yl)-1H-indol-5-ol with

-   -   butylamine gives        8-(1-methylpiperidin-4-yl)-2-propyl-6H-oxazolo[4,5-e]indole; ESI        298; salt precipitation with 1N HCl solution gives        8-(1-methylpiperidin-4-yl)-2-propyl-6H-oxazolo[4,5-e]indole        hydrochloride; benzylamine gives        8-(1-methylpiperidin-4-yl)-2-phenyl-6H-oxazolo[4,5-e]indole; ESI        332; salt precipitation with 1N HCl solution gives        8-(1-methylpiperidin-4-yl)-2-phenyl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   2-thiophen-2-ylethylamine gives        8-(1-methylpiperidin-4-yl)-2-thiophen-2-ylmethyl-6H-oxazolo[4,5-e]indole;        ESI 352; salt precipitation with 1N HCl solution gives        8-(1-methylpiperidin-4-yl)-2-thiophen-2-ylmethyl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   N¹,N¹-dimethylpropane-1,3-diamine gives        dimethyl{2-[8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indol-2-yl]ethyl}-amine;        ESI 327; salt precipitation with 1N HCl solution gives        dimethyl{2-[8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indol-2-yl]ethyl}-amine        hydrochloride;    -   2-(6-methoxy-1H-indol-3-yl)ethylamine gives        2-(6-methoxy-1H-indol-3-ylmethyl)-8-(1-methylpiperidin-4-yl)-6H-oxazolo-[4,5-e]indole;        ESI 416; salt precipitation with 1N HCl solution gives        2-(6-methoxy-1H-indol-3-ylmethyl)-8-(1-methylpiperidin-4-yl)-6H-oxazolo-[4,5-e]indole        hydrochloride;    -   C-benzo[b]thiophen-3-ylmethylamine gives        2-benzo[b]thiophen-3-yl-8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indole;        ESI 389; salt precipitation with 1N HCl solution gives        2-benzo[b]thiophen-3-yl-8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indole        hydrochloride;    -   methylamine gives        8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indole; ESI 256;        salt precipitation with 1N HCl solution gives        8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indole        hydrochloride;    -   1-(3-aminopropyl)pyrrolidin-2-one        1-{2-8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indol-2-yl]ethyl}pyrrolidin-2-one;        ESI 367; salt precipitation with 1N HCl solution gives        1-{2-8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indol-2-yl]ethyl}pyrrolidin-2-one        hydrochloride;    -   3-morpholin-4-ylpropylamine gives        8-(1-methylpiperidin-4-yl)-2-(2-morpholin-4-ylethyl)-6H-oxazolo[4,5-e]indole;        ESI 369; salt precipitation with 1N HCl solution gives        8-(1-methylpiperidin-4-yl)-2-(2-morpholin-4-ylethyl)-6H-oxazolo[4,5-e]indole        hydrochloride;    -   3-(4-methylpiperazin-1-yl)propylamine gives        2-[2-(4-methylpiperazin-1-yl)ethyl]-8-(1-methylpiperidin-4-yl)-6H-oxazolo-[4,5-e]indole;        ESI 383; salt precipitation with 1N HCl solution gives        2-[2-(4-methylpiperazin-1-yl)ethyl]-8-(1-methylpiperidin-4-yl)-6H-oxazolo-[4,5-e]indole        hydrochloride;    -   3-imidazol-1-ylpropylamine gives        2-(2-imidazol-1-ylethyl)-8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indole;        ESI 350; salt precipitation with 1N HCl solution gives        2-(2-imidazol-1-ylethyl)-8-(1-methylpiperidin-4-yl)-6H-oxazolo[4,5-e]indole        hydrochloride;    -   pyridin-3-ylmethylamine gives        8-(1-methylpiperidin-4-yl)-2-pyridin-3-yl-6H-oxazolo[4,5-e]indole;        ESI 333; salt precipitation with 1N HCl solution gives        8-(1-methylpiperidin-4-yl)-2-pyridin-3-yl-6H-oxazolo[4,5-e]indole        hydrochloride.

EXAMPLE 5

Analogously to Example 1, reaction of 3-piperidin-4-yl-1H-indol-5-olwith

-   -   2-thiophen-3-ylethylamine gives        8-piperidin-4-yl-2-thiophen-3-ylmethyl-6H-oxazolo[4,5-e]indole;        ESI 338; salt precipitation with 1N HCl solution gives        8-piperidin-4-yl-2-thiophen-3-ylmethyl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   2-thiophen-2-ylethylamine gives        8-piperidin-4-yl-2-thiophen-2-ylmethyl-6H-oxazolo[4,5-e]indole;        ESI 338; salt precipitation with 1N HCl solution gives        8-piperidin-4-yl-2-thiophen-2-ylmethyl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   pyridin-3-ylmethylamine gives        8-piperidin-4-yl-2-pyridin-3-yl-6H-oxazolo[4,5-e]indole; ESI        319; salt precipitation with 1N HCl solution gives        8-piperidin-4-yl-2-pyridin-3-yl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   N¹,N¹-dimethylpropane-1,3-diamine gives        dimethyl[2-(8-piperidin-4-yl-6H-oxazolo[4,5-e]indol-2-yl)ethyl]amine;        ESI 313; salt precipitation with 1N HCl solution gives        dimethyl[2-(8-piperidin-4-yl-6H-oxazolo[4,5-e]indol-2-yl)ethyl]amine        hydrochloride;    -   2-(6-methoxy-1H-indol-3-yl)ethylamine gives        2-(6-methoxy-1H-indol-3-ylmethyl)-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole;        ESI 401; salt precipitation with 1N HCl solution gives        2-(6-methoxy-1H-indol-3-ylmethyl)-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   C-benzo[b]thiophen-3-ylmethylamine gives        2-benzo[b]thiophen-3-yl-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole;        ESI 374; salt precipitation with 1N HCl solution gives        2-benzo[b]thiophen-3-yl-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   1-(3-aminopropyl)pyrrolidin-2-one        1-[2-(8-piperidin-4-yl-6H-oxazolo[4,5-e]indol-2-yl)ethyl]pyrrolidin-2-one;        ESI 353; salt precipitation with 1N HCl solution gives        1-[2-(8-piperidin-4-yl-6H-oxazolo[4,5-e]indol-2-yl)ethyl]pyrrolidin-2-one        hydrochloride;    -   3-morpholin-4-ylpropylamine gives        2-(2-morpholin-4-ylethyl)-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole;        ESI 355; salt precipitation with 1N HCl solution gives        2-(2-morpholin-4-ylethyl)-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   3-(4-methylpiperazin-1-yl)propylamine gives        2-[2-(4-methylpiperazin-1-yl)ethyl]-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole;        ESI 368; salt precipitation with 1N HCl solution gives        2-[2-(4-methylpiperazin-1-yl)ethyl]-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   3-imidazol-1-ylpropylamine gives        2-(2-imidazol-1-ylethyl)-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole;        ESI 336; salt precipitation with 1N HCl solution gives        2-(2-imidazol-1-ylethyl)-8-piperidin-4-yl-6H-oxazolo[4,5-e]indole        hydrochloride;    -   methylamine gives 8-piperidin-4-yl-6H-oxazolo[4,5-e]indole; ESI        242; salt precipitation with 1N HCl solution gives        8-piperidin-4-yl-6H-oxazolo[4,5-e]indole hydrochloride.

EXAMPLE 6

Analogously to Example 1, reaction of 3-piperidin-3-yl-1H-indol-5-olwith

-   -   butylamine gives        8-piperidin-3-yl-2-propyl-6H-oxazolo[4,5-e]indole; ESI 284; salt        precipitation with 1N HCl solution gives        8-piperidin-3-yl-2-propyl-6H-oxazolo[4,5-e]indole hydrochloride.

The examples below relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised and sealed under sterile conditions. Eachinjection vial contains 5 mg of active ingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I is meltedwith 100 g of soya lecithin and 1400 g of cocoa butter, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄×2 H₂O, 28.48 g of Na₂HPO₄×12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the general formula I

in which R¹ is H or Het¹, R² is H, A, cycloalkyl, —(CH₂)_(p)—N(R⁵)₂,—(CH₂)_(p)—OR⁵, —(CH₂)_(n)—Ar or —(CH₂)_(n)-Het, R³ is H, Hal, OH, OA orO—(CH₂)_(n)—Ar, R⁴ is H, A or —(CH₂)_(n)—Ar, R⁵ is H or A, A is a linearor branched alkyl group having from 1 to 10 carbon atoms, Ar is phenyl,naphthyl or biphenyl, each of which is unsubstituted or monosubstitutedor polysubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂,NR⁵COR⁵, NR⁵CON(R⁵)₂, NR⁵SO₂A, COR⁵, SO₂NR⁵ or S(O)_(m)A, cycloalkyl iscycloalkyl having from 3 to 10 carbon atoms, Hal is F, Cl, Br or I, Hetis a saturated, unsaturated or aromatic monocyclic or bicyclicheterocyclic radical having from 5 to 10 ring members, which may containfrom 1 to 4 N and/or from 1 to 4 S and/or from 1 to 4 O atoms, and inwhich the heterocyclic radical may be monosubstituted, disubstituted ortrisubstituted by Hal, A, —[C(R⁵)₂]_(o)—Ar, —[C(R⁵)₂]_(o)-cycloalkyl,OR⁵, N(R⁵)₂, NO₂, CN, COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵CON(R⁵)₂, NR⁵SO₂A,COR⁵, SO₂NR⁵ or S(O)_(m)A and/or carbonyl oxygen, Het¹ is a saturated,unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocyclicradical having from 5 to 10 ring members which contains at least 1 Natom and in which the heterocyclic radical may be monosubstituted,disubstituted or trisubstituted by Hal, A, OR⁵, N(R⁵)₂, NO₂, CN and/orcarbonyl oxygen, n is 0, 1, 2, 3, 4, 5, 6, 7 or 8, m is 1 or 2, o is 0,1, 2, 3 or 4, p is 1, 2, 3, 4, 5, 6, 7 or 8, and their physiologicallyacceptable salts and solvates.
 2. Compounds of the formula I accordingto claim 1, in which R⁴ is hydrogen.
 3. Compounds of the formula Iaccording to claim 1, in which R³ is hydrogen.
 4. Compounds of theformula I according to claim 1, in which R¹ is hydrogen,1-azabicyclo[2.2.2]oct-3-yl, piperidin-3-yl, piperidin-4-yl or1-methylpiperidin-4-yl.
 5. Compounds of the formula I according to claim1, in which R² is hydrogen, A, cycloalkyl, phenyl, o-methoxyphenyl,pyridin-3-yl, thien-2-yl, benzo-1,3-dioxol-5-yl, tetrahydrofuran-2-yl,benzothien-3-yl, methoxymethyl, thien-3-ylmethyl,6-methoxy-1H-indol-3-ylmethyl, 2-dimethylaminoethyl,morpholin-4-ylethyl, 2-oxopyrrolidin-1-ylethyl,(4-methyl)piperidin-1-ylethyl or imidazol-1-ylethyl, A is alkyl havingfrom 1 to 10 carbon atoms, and cycloalkyl is cycloalkyl having from 3 to10 carbon atoms.
 6. Compounds of the formula I according to claim 1 a)8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(5-methoxy-1H-indol-3-ylmethyl)-6H-oxazolo[4,5-e]indole;b) 8-(1-methylpiperidin-4-yl)-2-propyl-6H-oxazolo[4,5-e]indole; c)8-piperidin-4-yl-2-thiophen-2-ylmethyl-6H-oxazolo[4,5-e]indole; d)8-(1-azabicyclo[2.2.2]oct-3-yl)-2-thiophen-2-ylmethyl-6H-oxazolo[4,5-e]indole;e)8-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-imidazol-1-ylethyl)-6H-oxazolo[4,5-e]indole;f) 2-[2-(4-methylpiperazin-1-yl)ethyl]-6H-oxazolo[4,5-e]indole or theirphysiologically acceptable salts or solvates.
 7. Process for thepreparation of compounds of the formula I according to claim 1,characterised in that a compound of the formula II

in which R¹, R³ and R⁴ are as defined in claim 1, is reacted with acompound of the formula IIIH₂N—CH₂—R²   III, in which R² is as defined in claim 1, in the presenceof an oxidant, and if desired, the radical R¹═H is converted intoanother radical R¹, as defined in claim 1, and/or a base of the formulaI obtained is converted into one of its salts by treatment with an acid.8. Compounds of the formula I according to claim 1, and theirphysiologically acceptable salts and solvates as medicament activeingredients.
 9. Compounds of the formula I according to claim 1 andtheir physiologically acceptable salts or solvates as ligands of thenicotinic acetylcholine receptor.
 10. Compounds of the formula Iaccording to claim 1 and their physiologically acceptable salts orsolvates as serotonergic ligands.
 11. Pharmaceutical preparation,characterised by a content of at least one compound of the formula Iaccording to claim 1 and/or one of its physiologically acceptable saltsor solvates.
 12. Use of compounds of the formula I according to claim 1and/or their physiologically acceptable salts or solvates for thepreparation of a medicament.
 13. Use of compounds of the formula Iaccording to claim 1 and/or of their physiologically acceptable salts orsolvates for the preparation of a medicament for the treatment ofdisorders in which the binding to nicotinic acetylcholine receptorsresults in an improvement in the clinical picture.
 14. Use of compoundsof the formula I according to claim 1 and/or of their physiologicallyacceptable salts or solvates for the preparation of a medicament for theprophylaxis or treatment of psychoses, schizophrenia, depression,anxiety states, dementia, in particular Alzheimer's disease and Lewybodies dementia, neurodegenerative disorders, Parkinson's disease,amyotrophic lateral sclerosis, Huntington's disease, Tourette'ssyndrome, learning and memory restrictions, bulimia, anorexia nervosa orother eating disorders, compulsive behaviour, premenstrual syndrome,age-induced memory impairment, amelioration of withdrawal symptoms innicotine dependence, strokes or brain damage by toxic compounds.
 15. Useof compounds of the formula I according to claim 1 and/or of theirphysiologically acceptable salts and solvates for the preparation of amedicament for the treatment of disorders which are characterised by anexcess of circulating serotonin or by serotonergic hyperactivity.